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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5874_Библиотеки_им_академика_М_И_Перельмана
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β- Carbolines
FIGURE 8.6 Structure of different types of β- carbolines.
can range from dysthymia and a chronic low mood syndrome to serious depression,
which is typically accompanied by additional mental health issues like anxiety, sleeplessness, and obsessive behaviors and social phobia (Gold et al. 2015). The antidepressant effect of β- carbolines received attention from the scientic community due to the
actions on the monoamine neurotransmission, particularly the serotoninergic system
(Heshmati et al. 2014). β- carboline derivatives (Figure 8.6) for intense canthin- 6- ones
and bis- β- carbolines were separated from Picrasma. quassioides displayed promising
anti- inammatory properties (Yang et al. 2011).
In this chapter, we discuss the advancement of synthetic pathways for production
of β- carboline derivatives and their pharmacological potential as anti- inammatory
and antidepressant agents.
8.2 SYNTHESIS OF β- CARBOLINE AND ITS DERIVATIVES
Many literature studies have been done on β- carbolines and their derivatives based on
their role in natural products in the past couple of decades. β- carboline has been to
be a found a key component in several natural products and drugs. Several synthetic
protocols have been reported but the Pictet– Spengler method is the most promising
protocol; however, other methods are also producing novel β- carbolines that have
great importance due to theeir heterocyclic moiety.
Viswanathan et al. developed a protocol for the synthesis of β- carboline
derivatives that involved reaction of an appropriate amount of tryptamine and aldehyde that were heated using microwave radiation, and the resulting mixture was then
precipitated as salt of either a triuoroacetic acid or a hydrochloride (Viswanathan
et al. 2023). This tetrahydro- β- carboline salt is extracted by ltration, then it is
dissolved in dimethyl formamide and heated in the existence of lithium and silver
carbonates to produce the product β- carboline, which is then rened using ash
chromatography (Scheme 8.1).
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SCHEME 8.1 Microwave- assisted preparation of derivatives of β- carbolines.
SCHEME 8.2 Microwave- assisted preparation of β- carboline derivatives.
Eagon et al. demonstrated the microwave- assisted preparation of β- carboline within
20 minutes (Eagon et al. 2014). In this synthesis tryptamine served as the starting
material for the microwave- assisted Pictet– Spengler reaction, which produced a yield
of up to 99% utilizing 1,2- dichloroethane (DCE) and triuoroacetic acid (TFA) as
solvents (Scheme 8.2). Following the initial THBC synthesis, Pd/ C in EtOH was
used to produce tetrahydro- β- carboline salts, which were then aromatized to produce
β- carboline salts.
The synthesis of phenyl piperazine derivatives of β- carboline was reported by
Ashok et al. in which DL- tryptophan was used as a starting ingredient (Ashok et al.
2019). Following this, aldehyde conjugation and esterication with thionyl chloride
produced 1- substituted THBC ester. Following that, the β- carboline ester was produced
by oxidizing it with potassium permanganate in THF, and alkali hydrolysis produced
the β- carboline carboxylic acid. Finally, the preparation of diverse 3- substituted- β-
carboline phenyl piperazines (Scheme 8.3) was achieved by acid amide coupling with
a variety of substituted phenyl piperazines in the existence of EDC, HCl, and HOBt.
Maestri et al. studied the use of a palladium catalyst for the chemo- and regioselective
synthesis of tetrahydro β- carbolines. Co- catalysis of palladium and carboxylic acid at
100°C using phosphine as a ligand in toluene, with complete conguration control in
every scenario, results in the creation of C- C bonds via indolic C(SP2)- H bond activation of N- propylated tryptamines, recovering products as a single E- isomer (Cera
et al. 2018) (Scheme 8.4).
Another new, extremely effective protocol for the preparation of aromatic β-
carbolines from 2- acyl- 3- bromoindoles employing tributyl [(Z)- 2- ethoxyvinyl]
stannane as a C2 building block via Stille cross- coupling was developed by Kamlah
et al. (2015) The synthesis of β- carbolines occurred in modest yields in the rst Pdcatalyzed step, which was succeeded by the ring closure in glacial acetic acid using
NH4OAc (Scheme 8.5).
One- pot bimetallic relay catalysis and one- pot triple- orthogonal metal relay
catalysis were devised by Dhiman et al. for the preparation of 1,3- disubstituted 4hydroxy β- carbolines and 1,3- disubstituted β- carbolines (Dhiman et al. 2016). Both
cases began with the easily available 3- (2- aminophenyl)- 5- hexenyn- 3- ols as raw
ingredients (Scheme 8.6).
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β- Carbolines
SCHEME 8.3 Preparation of β- carbolines derivatives.
SCHEME 8.4 Preparation of β- carbolines with palladium assistance.
SCHEME 8.5 Pd- catalyzed preparation of β- carboline derivatives.
SCHEME 8.6 A method of making β- carbolines in a single pot.
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SCHEME 8.7 BF3.OEt2- catalyzed synthetic approach for the synthesis of β- Carboline
derivative.
SCHEME 8.8 MeOTf- catalysed synthetic pathway for the synthesis of β- Carboline derivative.
SCHEME 8.9 TFA catalyzed synthetic route for the synthesis of β- Carboline derivatives.
In another protocol, He et al. described a facile synthesis of β- carboline derivatives
at 25oC for 12 hours with a good yield (80%) (He et al. 2016). In this protocol, the
intended product was produced using dichloro methane (DCM) as a polar aprotic
solvent and borontriuoride etherate (BF3.OEt2) as a Lewis acid catalyst during
the indole oxazolone cyclization process (Scheme 8.7). However, this simple one-
pot method produces 80% of the therapeutically important tetrahydroisoquinoline
alkaloids found in nature.
In 2017, Wen et al. demonstrated a simple and efcient protocol for the formation
of β- carboline derivatives in a non- polar solvent like DCE at 80°C with 90% yield of
product (Wen et al. 2017) under catalytic media of isothiocyanate and methyltriuoro
methanesulfonate (MeOTf) (Scheme 8.8). This synthetic process is used to make the
traditional Chinese medicine drug rutacarpine (an alkaloid quinazolinone), which is
useful for treating diseases associated with inammation.
Spindler et al. presented a straightforward, all- purpose, capable, and practical
route at room temperature for the synthesis of 1- substituted tetrahydro- β- carbolines
with a superior yield range (18– 97%) (Spindler et al. 2016). The Pictet– Spengler
reaction using tryptamine derivatives and aldehyde, together with a suitable catalyst
such triuoroacetic acid (TFA), can be used to carry out this method over the course
of 24 hours in a polar DCM solvent (Scheme 8.9).
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β- Carbolines
SCHEME 8.10 β- Carboline derivative synthetically prepared using I2 catalysis.
SCHEME 8.11 Synthesis of β- carbolines via bases.
SCHEME 8.12 The use of TFA in the synthesis of a derivative of β- carboline.
An efcient protocol for the synthesis of β- carboline derivative based on Pictet-
Spengler condition with moderate yield range (60– 85%) was developed by Battini
et al. (2014). In this protocol, tryptophan methyl ester was reacted with an aldehyde
derivative at a temperature of 90°C in the presence of molecular iodine (I2)
as a catalyst and polar aprotic solvent dimethylsulfoxide (DMSO) (Scheme 8.10).
The demonstrated catalytic pathway is competent, cost- effective, and incredibly
selective; it yields a high spectrum of β- carboline derivatives, ranging from 60– 85%,
and concludes without the need for any protective groups for the separation and processing of these compounds.
Puried 2- aminobiaryls produced the best results, yielding β- carbolines in an
excess of 18– 66% yield reported by Shainthavaan et al. when they were combined
with an excess of NaHMDS. As far as we are aware, this reaction process, which
begins with commercially available 3- uoropyridines, offers the fastest way to
synthesize the naturally occurring carbolines norharmane (Sathiyalingama et al.
2022) (Scheme 8.11).
A straightforward and effective approach for the synthesis of β- carboline
derivatives with an appreciable yield range of 81– 96% was developed by Singh et al.
(2012). This method can be carried out at room temperature by reacting tryptamine
with an aldehyde derivative for 3 to 4 days in the existence of TFA as an acid catalyst
and DCM as a solvent to produce a derivative of β- carboline (Scheme 8.12). This
protocol’s benets include simplicity, cost- effectiveness, and a typically important
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SCHEME 8.13 POCl3 catalyzed synthetic path for β- Carboline derivative in acetonitrile
solvent.
SCHEME 8.14 Synthesis for β- Carboline derivative in toluene, accelerated by POCl3.
SCHEME 8.15 A synthetic process for producing derivatives of β- carboline using the MeOTf
catalyst.
reaction with as superb yield (81– 96%). Additionally, the derivative encourages a
variety of fused and substituted- β- carbolines that operate as bioactive agents.
Saha et al. developed an efcient synthetic route of Bischler– Napieralski cyclized
β- carboline derivative (Saha et al. 2011). Using phosphoryl chloride (POCl3) as a
Lewis acid catalyst and a polar aprotic solvent such acetonitrile, tryptamine amide
was cyclized using this approach for a period of 24 hours at a temperature of 120oC
with an excellent yield (70%) (Scheme 8.13).
A subsequent synthesis of β- carboline derivative was reported by Saha et al.
(2011). Using POCl3 and tryptamine amide for 12 hours under reux conditions in a
nonpolar solvent such as toluene yielded a product with a respectable percentage of
45% (Scheme 8.14). The benet of this POCl3 promoted synthetic technique is the
straightforward, affordable, and one- pot procedure.
Wen et al. established a protocol at 80°C for the synthesis of an isothiocyanatederived β- carboline derivative using methyltriuoro methanesulfonate (MeOTf) as a
catalyst in a nonpolar solvent such as DCE (Wen et al. 2017). This method produced
an outstanding yield of 90%. In traditional Chinese medicine, the quinazolinone
alkaloid rutaecarpine is used to treat inammation- related illnesses and is synthesized
using this method (Scheme 8.15).
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β- Carbolines
SCHEME 8.16 Economically benecial process for making β- carbolines.
SCHEME 8.17 Ruthenium- catalyzed synthesis of β- carboline derivatives.
A two- step, economically advantageous method for producing β- carbolines was
described by Dhara et al. (2014). N- tosylated 2- iodoanilines were coupled with 2-
chloropyridin- 4- yl- boronic acid precursors in the Suzuki reaction. Following ring
closure brought about by Pd- mediated C- H/ N- H activation, a modest yield of the
intended product was obtained (Scheme 8.16).
Witulski et al. created a quick ruthenium- catalyzed process for creating the
skeleton of the β- carboline (Witulski et al. 2011). Starting with readily accessible
2- iodoaniline, the necessary yne- ynamides were made in ve steps (Scheme 8.17).
The corresponding β- carbolines were produced by the [2+ 2+ 2] cyclo addition of
yneynamides with methyl cyanoformate under the inuence of CpRuCl(cod). The
marine alkaloid eudistomin U was successfully synthesized using this method.
A simple procedure to synthesize β- carboline compounds with palladium support
was described by Ding et al. (2010). This can be achieved by directly dehydrogenating internal alkynes and tert- butylimines of N- substituted indole carboxaldehydes
in an annulation reaction (Scheme 8.18). In this procedure, elemental oxygen was
employed to activate the C- H bond.
In another protocol, Wu et al. demonstrated one- pot preparation of β- carboline
derivative at 110oC temperature for 5– 10 h of duration time with excellent yield
(86%) (Zhu et al. 2013). This procedure can be carried out by reacting tryptamine
and aceophenone with molecular iodine (I2), hydrogen peroxide (H2O2), and a polar
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SCHEME 8.18 Pd catalysed synthesis of β- carboline compounds.
SCHEME 8.19 Preparation of a derivative of β- Carboline using of H2O2 and I2.
SCHEME 8.20 A single- pot synthesis of derivatives β- carbolines.
SCHEME 8.21 Synthetic route for the synthesis of functionalized tetrahydro β- carbolines
derivatives.
aprotic solvent like DMSO (Scheme 8.19). The result is pityriacitrin (a derivative of
the amino acid carboline).
Wang et al. reported a unique one- pot preparation of β- carbolines (Wang et al.
2018). The planned synthesis, which begins with racemic tryptophan and different
amino acids, progresses in a series of stages that include decarboxylation, deamination, the Pictet– Spengler reaction, and oxidation (Scheme 8.20). These steps are
driven by a reaction with I2 and TFA.
Zeng et al. effectively developed a “two- in- one” approach to synthesize
functionalized tetrahydro β- carbolines by palladium- catalyzed C- H bond activation
of tryptamines with carbonyl compounds in water, which involves in situ imine production as a guiding group (Zeng et al. 2019) (Scheme 8.21) to develop a transformative protocol that is more atom- economic and environmentally friendly.
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β- Carbolines
SCHEME 8.22 Synthesis of β- carbolines with microwave assistance, supported by TFA.
SCHEME 8.23 By virtue of water synthetic route for a derivative of β- carboline.
A microwave- assisted protocol designed by Anderson et al. involves Pictet–
Spengler synthesis to obtain β- carboline (Anderson et al. 2014). In order to obtain the
(70– 99%) yield range of the product, tryptamine is allowed to react with substituted
aldehyde and 2,2- dimethoxypropane (CH(OME)2) in the presence of TFA as an acid
catalyst in a mobile solvent like 1,2- dichloroethane (DCE) under acidic conditions
containing hydrochloric acid (HCl) at 110oC temperature for 20 min (Scheme 8.22).
The primary advantage of this method is its ability to quickly and easily manufacture
pure crystalline products on a milligram to gram scale through precipitation after
simple ltration, with a high yield range of 70– 99%, all without the need for liquid
liquid extraction or column chromatography.
An efcient and greener methodology for the synthesis of β- carboline derivatives
was developed by Buxi et al. which yielded a good yield range (50– 83%) using the
Pictet– Spengler condensation reaction of L- tryptophan with aldehyde derivative in
water as a green solvent under reux conditions for 3 hours (Buxi et al. 2013) (Scheme
8.23). This method is cost- effective, effective, and uses water as a green solvent.
Ame Pictet and Theodor Spengler developed a process for producing substitutions
or fused beta- carbolines by articial synthetic methods (Royer et al. 2004). They
produced a protocol to synthesize 1,2,3,4- tetrahydroisoquinoline by heating
phenylethylamine with aldehyde in the existence of acidic media. An imine is
produced by the Pictet- Spengler reaction, which then cycles electron- rich aryl or
heteroaryl groups onto imine or iminium ion electrophiles to yield an iminium ion in
an acidic environment (Scheme 8.24). The same method has been used for the preparation of a variety of aza- heterocyclic compounds (Tatsui et al. 1928).
The biosynthesis of β- carboline alkaloids was achieved by the formation of Schiff
base of tryptamine and then subsequent intramolecular Mannich reaction, in which
the C2- carbon of indole ring behave as a nucleophile (França et al. 2014). Further the
aromaticity of the nucleus was regenerated via abstraction of a proton from the C2.
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SCHEME 8.24 Pictet- Spengler reaction for the synthesis of β- carboline.
SCHEME 8.25 Biosynthesis of fully aromatic beta- carboline from tryptamine.
Finally, the desired compound (Rajesh et al. 2019) i.e. fully aromatic β- carboline is
obtained by the oxidation of 3,4- dihydro- β- carboline (Scheme 8.25).
Yang et al. described the synthesis of β- carboline by the condensation of pyruvic
aldehyde with L- tryptophan or L- tryptophanylamide (Yang et al. 2006). Similar
products could be obtained by the coupling reaction between 4- methoxyphenylglyoxal
and tryptophan methyl ester. Changing the functionalities from carboxylic acid group
to amide (Mei- L et al. 2011) and ester signicantly increased the yields of the desired
products (Scheme 8.26).
A facile and environmentally friendly method has been developed in a single
step from tryptamine and aldehydes for the preparation of tetrahydro- β- carbolines
(tryptolines) (Hong- J et al. 2020). The preparation of diverse tryptolines derivatives
was catalyzed by L- tartaric acid, a natural existing compound used to achieve the
desired products in form of colourless crystals. This new protocol of synthesis
using water and L- tartaric acid is easy, safe, and inexpensive, and the products can
be easily separated using basic ltration method as they are obtained in crystals
(Scheme 8.27).
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